This program project centers on the molecular and cellular basis of the autoimmune response. There are five investigators (in Paul Allen, Osami Kanagawa, Ken Murphy, Stacy Smith and Emil Unanue) involved in three large projects, and a mass spectrometry core support, directed by Dr. M. Gross. As a group, we are studying the nature of the T cell response to autologous peptides associated with the class I or II MHC molecules of antigen presenting cells. We are taking advantage of experiences, expertise and technologies gathered from the analysis of model protein antigens, applying them to autoimmune problems. The project headed by Unanue and Kanagawa jointly studies the autoimmune diabetes of NOD mice. It examines the distribution of protein antigens that trigger CD4 and CD8 T cells and the nature of the peptides that bind to I-Ag7. Evaluated are binding motifs, the issues of affinity and MHC stability and the issues of major and minor epitopes from beta cell antigens. The project headed by Drs. Allen and Smith continues analysis of autoimmune reactions in the heart. Considered are the issues of the characterization of the myosin peptides that trigger myocarditis, the activation events required to initiate autoimmune myocarditis, and the relationship between self- tolerance and molecular mimicry. Dr. Murphy's project centers on how CD4 T cell subset differentiation takes place. He continues examining T cells from TcR transgenic mice, probing both the cellular and molecular control of differentiation, in particular the role of peptide structure in selection and of the cytokines IL-12 and IFN-gamma; and the molecular biology of IL-12 action. All three projects will create transgenic mice bearing Tc receptor genes from CD4 and/or CD8 T cells. These will be invaluable for examining the role of T cell in the dynamics of autoimmunity. The mass spectrometry component is essential for the following projects: i) the characterization of peptides from the diabetogenic antigens associated with class I or II MHC of NOD mice; ii) the analysis of the repertoire of self-peptides isolated from Ag7 and iii) the analysis of peptides from myosin associated with the class II MHC molecules.